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[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The recognition of an early form of glandular neoplasia termed atypical adenomatous hyperplasia (AAH), a precursor lesion from which lung adenocarcinomas arise, provides an opportunity for characterizing early epigenetic alterations involved in lung tumorigenesis.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Atypical adenomatous hyperplasia (AAH) is postulated to be the earliest morphologic precursor lesion in lung carcinogenesis.

The epidermal growth factor receptor (EGFR), one of the members of the Erb-2 family of receptors, is commonly expressed in non-small celllung carcinoma (NSCLC).

Recent reports show that EGFR mutations are rare or absent in AAH and are rare in bronchioloalveolar carcinoma (BAC).

In this study, we examined the EGFR gene copy number status in lung adenocarcinomas, synchronous AAH, and BAC in surgical pathology resection specimens.

In our cohort, the rate of EGFR gene copy abnormalities in AAH appears similar to BAC and lower than in lung adenocarcinomas.

These findings suggest that although EGFR gene copy abnormalities may be an early event in lung carcinogenesis, they are associated with tumor progression to invasive cancer and highlight the complexity of tumor morphogenesis.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] CT findings of atypical adenomatous hyperplasia in the lung.

OBJECTIVE: The aim of this study was to analyze the computed tomographic (CT) findings of atypical adenomatous hyperplasia (AAH) in the lung.

The CT findings of each AAH lesion were evaluated for multiplicity, location, shape, size and internal density of the lesion, the interface between the normal lung and the lesion, the internal features within the lesion and any change of the lesion on the follow-up CT scans (range: 33 to 540 days; average: 145.3 days).

Four of them (50%) had synchronous malignancies in the lung: adenocarcinoma of the lung (n = 3), and metastatic squamous cell carcinoma from the uterus (n = 1).

CONCLUSION: Atypical adenomatous hyperplasia is often associated with malignancy.

We previously found that most (88%) pure nonmucinous bronchioloalveolar carcinomas (adenocarcinoma in situ) already harbor EGFR mutations, indicating that the mutations are an early genetic event in the pathogenesis.

We examined 54 atypical adenomatous hyperplasias, precursor lesions of lung adenocarcinomas, obtained from 28 Japanese patients for the hotspot mutations of EGFR exons 19 and 21 and K-ras codon 12.

We did not observe apparent histological differences between atypical adenomatous hyperplasias with and without EGFR mutations.

K-ras mutation (G12S) was detected in only one atypical adenomatous hyperplasia.

As EGFR mutational frequency of atypical adenomatous hyperplasias was much lower than that of nonmucinous bronchioloalveolar carcinomas, we surmise that EGFR-mutated atypical adenomatous hyperplasias, but not atypical adenomatous hyperplasias with wild-type EGFR, are likely to progress to nonmucinous bronchioloalveolar carcinomas.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

BACKGROUND: The mechanisms of generation and progression of multicentric lung adenocarcinoma (AD), bronchioloalveolar carcinoma (BAC), and atypical adenomatous hyperplasia (AAH) in the peripheral lung is not well known.

(2) LAT1 mRNA and protein expressions in 35 normal lung tissues, 34 AAH (11 lesions were interpreted as low-grade AAH and 23 as high-grade AAH), and 43 NMBAC using in situ hybridization and immunohistochemistry; and (2) the association of the incidences of LAT1 mRNA and protein expressions with cell proliferation in these lesions.

The level of LAT1 mRNA/GAPDH mRNA (1) tended to be higher in NMBAC (12.0+/-8.1) than in normal lung tissues (1.0+/-0.2), and (2) covered a much wider range (from 0 to 276) in NMBAC than in normal lung tissues (from 0 to 5.8), with six NMBAC having values higher than 7.0, while 5.8 was the highest value detected in normal lung tissues.

In peripheral normal lung tissues, LAT1 mRNA and protein were detected in bronchial surface epithelial cells and alveolar macrophages (but not in nonciliated bronchiolar epithelial cells, or in alveolar type I or type II cells).

The Ki-67 labeling index (a cell proliferation score) was significantly higher in those AAH and NMBAC that were LTA1-protein-positive than in their LAT1-protein-negative counterparts.

In conclusion, LAT1 expression may increase with the upregulation of metabolic activity and cell proliferation in high-grade AAH and NMBAC.

[Title] Mre11 expression in atypical adenomatous hyperplasia and adenocarcinoma of the lung.

CONCLUSIONS: On this basis, we suggest that the part played by Mre11 in telomere maintenance may not be important for the progression of the adenoma-carcinoma (AAH-NMBAC) sequence in the lung, although some role for it in carcinogenesis cannot be completely ruled out.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Atypical adenomatous hyperplasia (AAH) has been recently defined by WHO as a small lesion, not exceeding 5mm in major axis, composed of slightly enlarged alveolar septa lined by pneumocytes with plump, atypical nuclei.

AAH is frequently found in tissue surrounding lung adenocarcinoma and is considered a precursor of this subtype of lung cancer by many Authors.

Because the differentiation from multiple atypical adenomatous hyperplasia (AAH) was necessary, we finally performed a diagnosis of MMPH based on specimens obtained by video-assisted thoracoscopic surgery.

Although immunohistochemical stains for cytokeratin and surfactant apoprotein A and B were positive for alveolar lining cells in each MMPH lesion, those for HMB-45, alpha-smooth muscle actin, p53 and carcinoembryonic antigen were negative.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Association of CYP19A1 polymorphisms with risks for atypical adenomatous hyperplasia and bronchioloalveolar carcinoma in the lungs.

Estrogen has been indicated to play an etiological role in the development of lung adenocarcinoma (ADC), particularly bronchioloalveolar carcinoma (BAC), a type of ADC that develops from a benign adenomatous lesion, atypical adenomatous hyperplasia (AAH).

Associations of this SNP with risks for lung AAH and BAC in the lungs were next examined using 359 ADC cases whose resected lung lobes were subjected to a histological examination for AAH accompaniment and the presence of BAC components and 330 controls without cancer.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

OBJECTIVE: The purpose of our study was to investigate the differentiation between bronchioloalveolar carcinoma and atypical adenomatous hyperplasia manifesting pure ground-glass opacity (GGO) based on selected features on thin-section helical CT scans.

CT findings of atypical adenomatous hyperplasia and bronchioloalveolar carcinoma were compared using univariate and multivariate logistic regression analysis; the odds ratio was computed using the atypical adenomatous hyperplasia group as the reference group.

CONCLUSION: Nodular sphericity and an internal air bronchogram were useful at thin-section helical CT performed to differentiate between bronchioloalveolar carcinoma and atypical adenomatous hyperplasia.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The pulmonary adenoma susceptibility 1 (Pas1) gene affects susceptibility to the development of lung adenomas in mice with a subset of the adenomas progressing to adenocarcinoma (ADC).

In this study, genotype distributions for 10 polymorphisms in the human counterparts for three mouse candidate Pas1 genes, KRAS, CASC1/LAS1 and LRMP, were examined in a hospital-based case-control study consisting of 364 lung ADC cases and 253 controls.

All the ADC cases were subjected to lobectomy and subsequent pathological investigation of atypical adenomatous hyperplasia (AAH), a putative precursor for peripheral lung ADC, including bronchioloalveolar carcinoma, in the resected lobes.

Minor haplotypes including the minor allele for the KRAS-6 polymorphism showed increased ORs for ADC accompanied by multiple AAHs, and KRAS transcripts from the minor allele for this polymorphism were more abundantly detected in lung tissues than those from the major allele.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Disproportionate representation of KRAS gene mutation in atypical adenomatous hyperplasia, but even distribution of EGFR gene mutation from preinvasive to invasive adenocarcinomas.

In the resected lung, additional small lesions are occasionally found incidentally, and include the full spectrum of preinvasive to invasive lesions under the current putative schema of the sequential development of lung cancer.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Atypical adenomatous hyperplasia (AAH) is considered the preinvasive lesion of pulmonary adenocarcinoma, and mutations of EGFR, HER2, and K-ras are involved in the early stage of lung adenocarcinoma carcinogenesis, also predicting clinical response to anti-EGFR small molecule inhibitors.

[Title] Clinicopathologic analysis of multiple (five or more) atypical adenomatous hyperplasias (AAHs) of the lung: evidence for the AAH-adenocarcinoma sequence.

MATERIALS AND METHODS: The subjects were 1,639 patients who underwent lobectomy or pneumonectomy for lung tumors.

The clinicopathologic features of the AAHs in the lung background and the main tumors were examined with regard to the number and the size of the AAHs, the incidence and histology of adenocarcinomas (ADs), and the outcome.

CONCLUSION: Five or more AAHs were seen in the background in 2.0% of lung tumors.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Multifocal micronodular pneumocyte hyperplasia is a rare pulmonary manifestation of tuberous sclerosis complex (TSC) that is a tumor suppressor gene disorder characterized by many hamartomas.

Although multifocal micronodular pneumocyte hyperplasia develops locally as self-limited, benign lesions, it is morphologically similar to the preinvasive lesion of pneumocytes that characterize atypical adenomatous hyperplasia or bronchioloalveolar carcinoma.

The goal of this study was to determine whether multifocal micronodular pneumocyte hyperplasia is neoplastic.

The results showed that at least one of two multifocal micronodular pneumocyte hyperplasia lesions from each patient had loss of heterozygosity on TSC1 or TSC2 (15 or 50%) and were frequently immunopositive for phospho-mTOR (88%), phospho-p70S6K (100%), and phospho-S6 (100%) but not phospho-Akt (14%), an upstream regulatory protein of mTOR.

Loss of heterozygosity of TSC was found in the preinvasive lesions of pneumocytes, equal to or less than multifocal micronodular pneumocyte hyperplasia.

In contrast, phospho-Akt was expressed in the preinvasive lesions of pneumocytes more frequently than multifocal micronodular pneumocyte hyperplasia, but the other mTOR-related proteins were less frequently expressed in the former than in the latter.

These outcomes suggest that functional loss of TSCs and consequent hyperphosphorylation of mTOR-related proteins in multifocal micronodular pneumocyte hyperplasia may cause its benign neoplastic proliferation of pneumocytes.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Precursor lesions of adenocarcinoma lung--two case reports.

Although precursor lesions of bronchogenic squamous cell carcinoma are well documented, the preinvasive lesions of pulmonary adenocarcinoma are seen very rarely.

It has been hypothesized that there is a stepwise progression of alveolar epithelial hyperplasia to atypicalalveolarhyperplasia and subsequently to malignancy in the pathogenesis of peripheral adenocarcinoma of the lung.

In the present paper we would like to share our experience of two cases of pulmonary adenocarcinoma with their precursor lesions in the form of atypicalalveolarhyperplasia.

[Publication-type] Case Reports; Journal Article

[Publication-country] Japan

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title]Lung cancer preneoplasia.

From histological and biological perspectives, lung cancer is a complex neoplasm.

Although the sequential preneoplastic changes have been defined for centrally arising squamous carcinomas of the lung, they have been poorly documented for the other major forms of lung cancers, including small celllung carcinoma and adenocarcinomas.

There are three main morphologic forms of preneoplastic lesions recognized in the lung: squamous dysplasias, atypical adenomatous hyperplasia, and diffuse idiopathic pulmonary neuroendocrine cellhyperplasia.

However, these lesions account for the development of only a subset of lung cancers.

Two different molecular pathways have been detected in lung adenocarcinoma pathogenesis: smoking-associated activation of RAS signaling, and nonsmoking-associated activation of EGFR signaling; the latter is detected in histologically normal respiratory epithelium.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Immunohistochemical markers of cancerogenesis in the lung.

Lung cancer is the leading cause of cancer deaths for people of both sexes worldwide.

Early diagnosis of precancer lesions may be of crucial significance to lowering lung cancer mortality.

The World Health Organization has defined three preneoplastic lesions of the bronchial epithelium: squamous dysplasia and carcinoma in situ, atypical adenomatous hyperplasia and diffuse idiopathic pulmonary neuroendocrine cellhyperplasia.

These lesions are believed to progress to squamous cell carcinoma, adenocarcinoma and carcinoid tumors, respectively.

Apart from WHO classification, two other lesions such as bronchiolization and bronchiolar columnar cell dysplasia (BCCD) can be observed and thought to be preneoplastic lesions leading to adenocarcinoma.

In this review we summarize the data of morphological and cell cycle related proteins changes in both central and peripheral compartments of lung.

[Chemical-registry-number] 0 / Biomarkers, Tumor

[Number-of-references] 67

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Etiology, epidemiology, biology. Lung carcinogenesis].

Lung cancer is a complex disease involving various oncogenic pathways.

Pre-invasive stages exist for different forms of lung cancer and some of them are recognized as being preneoplastic: dysplasias and in situ carcinoma, atypical adenomatous hyperplasia and diffuse idiopathic pulmonary neuroendocrine cellhyperplasia are supposed to be precursors of squamous cell carcinomas, adenocarcinomas and carcinoid tumors, respectively.

The sequence of histological modifications of bronchial mucosa preceding the development of a squamous cell carcinoma are well documented while those preceding other histological types are less known.

It also discusses arguments for their preneoplastic nature, their evolution and risk of progression risk, molecular abnormalities involved in lung carcinogenesis and clinical relevance of these lesions.

[MeSH-major]Lung Neoplasms / pathology. Precancerous Conditions

[MeSH-minor] Humans. Hyperplasia. Lung / pathology

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[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Ground-glass opacities showing an adenoma-to-carcinoma sequence in the lung.

Pathological diagnoses of the resected lesions included a focus of atypical adenomatous hyperplasia (AAH) and two localized noninvasive bronchioloalveolar carcinomas (BACs) of types A and C according to Noguchi's classification.

This case supports the hypothesis of an adenoma-to-carcinoma sequence in the lung, as the coexisting lesions represented sequential adenocarcinoma progression from a precancerous lesion, AAH, to very early-stage adenocarcinoma, noninvasive BAC.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Overexpression of Dicer in precursor lesions of lung adenocarcinoma.

Differential microRNA (miR) expression is described in non-small celllung carcinoma. miR biogenesis requires a set of proteins collectively referred to as the miR machinery.

In the proposed multistep carcinogenesis model, peripheral adenocarcinoma of the lung develops from noninvasive precursor lesions known as atypical adenomatous hyperplasia (AAH) and bronchioloalveolar carcinoma (BAC).

Expanded immunohistochemical and Western blot analysis showed higher Dicer level in squamous cell carcinoma (SCC) of the lung when compared with adenocarcinoma.

Other proteins of the RNA-induced silencing complex (RISC; SND1, PACT, and FXR1) were also present at higher levels in a SCC cell line when compared with an adenocarcinoma cell line.

In conclusion, the stoichiometry of miR machinery and RISC depends on histologic subtype of lung carcinoma, varies along the AAH-BAC-adenocarcinoma sequence, and might explain the observed abnormal miR profile in lung cancer.

The status of the endogenous miR machinery in various histologic subtypes and stages of lung cancer may help to predict the toxicity of and susceptibility to future RNA interference-based therapy.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Neurokinin-1 receptor blockade and murine lung tumorigenesis.

RATIONALE: Analogous to the adenoma-carcinoma sequence in the colon, it has been proposed that adenocarcinoma (AC) in the lung arises from adenomatous hyperplasia that progresses through atypical adenomatous hyperplasia to AC.

We also demonstrate that a series of alterations in gene expression of proliferation markers (i.e., PCNA and Ki-67) and cell cycle regulators (i.e., FHIT, p53, and p21) characterizes the sequence of the precursor lesions.

The loss of function of the NK-1R results in changes of the apoptotic rate and in a delay of DNA break recovery of alveolar epithelial cells following bleomycin treatment.

CONCLUSIONS: To our knowledge, this is the first model to demonstrate a role for NK-1R in lung epithelial cell death and tumorigenesis.

When bronchioloalveolar carcinomas were present in a pure form or as a component of adenocarcinomas, positive insulin-like growth factor II mRNA binding protein 3 staining was always patchy, with less than 20% of tumor cells stained.

These findings show that insulin-like growth factor II mRNA binding protein 3 is strongly and diffusely expressed in a large proportion of moderately/poorly differentiated lung adenocarcinomas, in particular in the solid component of mixed subtype adenocarcinomas, less frequently expressed in well-differentiated adenocarcinomas and bronchioloalveolar carcinomas, and negative in atypical adenomatous hyperplasias.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Survivin is an inhibitor of apoptosis protein, which is overexpressed in many carcinomas, including lung carcinoma.

The aim of this immunohistochemical study was to investigate the role of survivin in the early steps of lung carcinogenesis and non-small celllung carcinomas (NSCLC), and its relationship with expression of p53 protein, a tumor suppressor gene involved in cell cycle control.

In conclusion, survivin expression might be an early step in lung carcinogenesis.

Survivin expression might also be used as a prognostic indicator predicting the worse outcome in NSCLC, and might be a novel target for the treatment of patients with preinvasive lesions of lung and NSCLC.

RESULTS: Immunohistochemical studies show that human bronchial dysplasia and atypical adenomatous hyperplasia express high levels of FAS compared with normal lung tissues, suggesting that FAS might be a target for intervention in lung carcinogenesis.

FAS is also expressed at high levels in chemically induced murine lung tumors, and the numbers and sizes of those murine tumors are significantly reduced by treating carcinogen-exposed mice with pharmacologic inhibitors of FAS, C75 and C93.

CONCLUSIONS: We conclude that increased levels of FAS are common in human preinvasive neoplasia of the lung.

Based on studies in mouse models, it seems that inhibiting FAS is an effective strategy in preventing and retarding growth of lung tumors that have high expression of this enzyme.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Sequential molecular changes during multistage pathogenesis of small peripheral adenocarcinomas of the lung.

INTRODUCTION: We investigated EGFR and KRAS alterations among atypical adenomatous hyperplasia and small lung adenocarcinomas with bronchioloalveolar features to understand their role during multistage pathogenesis.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Recent radiological scrutiny has enabled the identification of small peripheral lesions in the lung.

A chromosome-wide investigation encompassing almost all the chromosomal centromeres was performed using modified fluorescence in situ hybridization on the archived pathological samples of 16 atypical adenomatous hyperplasia (AAH) and 30 lung adenocarcioma (AdCa) specimens including those smaller than 1 cm in size.

The prevalence of the gain differed significantly between AAH and bronchioloalveolar carcinoma (BAC) </= 1 cm, but not between BAC < 1 cm and well-differentiated AdCa > 1 cm.

It is proposed that the CNA is a distinct phenomenon occurring in the early or premalignant stage of lung AdCa, and that the CNA itself may not be a sequel in the carcinogenetic process, but a driving factor in carcinogenesis.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] The ACIN1 gene is hypermethylated in early stage lung adenocarcinoma.

We hypothesized that characteristic aberrant hypermethylation of CpG islands of certain genes may exist in the early stages of lung adenocarcinoma and that such alterations may be useful in the detection and treatment of early lung adenocarcinoma.

METHODS: A pair of immortalized cell lines originating from atypical adenomatous hyperplasia (PL16T) and from the resected end of the bronchus of the same patient (PL16B) was searched for aberrantly and differentially hypermethylated DNA fragments by a combination of the methylated CpG island amplification and suppression subtractive hybridization methods.

A higher frequency of hypermethylation at a locus at the 5': end of the DNA fragment isolated from the ACIN1 gene was found in small-sized adenocarcinoma (2 cm or less) (30/37, 81%) compared with normal lung tissue (9/37, 24%, p < 0.05).

Interestingly, hypermethylation of ACIN1 was detected relatively frequently in the normal counterpart of adenocarcinoma without bronchioloalveolar carcinoma (BAC) component (7/16, 44%), but was rare in the normal counterpart of adenocarcinoma with BAC component (2/21, 10%, P < 0.05).

CONCLUSIONS: We found hypermethylation of the ACIN1 gene in early stage lung adenocarcinoma.

The role of methylation status in the development and malignant transformation of lung adenocarcinoma requires clarification.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The expression profile of adenoma induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in A/J mice was compared with that of normal lung tissue by suppression subtractive hybridization (SSH).

The mRNAs of surfactant-associated protein A (SP-A) and lysozyme showed characteristically higher transcription in the adenoma tissue than in normal lung.

In normal lung, alveolar type II pneumocytes were positive for both SP-A and lysozyme, indicating that tumor cells retained the phenotypic characteristics of the murine alveolar type II pneumocytes.

Previous studies of human adenocarcinomas have shown that the two proteins are expressed reciprocally; SP-A and lysozyme are differential markers of atypical adenomatous hyperplasia (AAH) and non-goblet cell type adenocarcinoma, and of goblet cell type adenocarcinoma, respectively.

Thus, the present results indicate that the phenotype of NNK-induced A/J mouse adenoma differs from that of AAH, which is thought to be a preinvasive lesion of human adenocarcinoma.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

BACKGROUND: Atypical adenomatous hyperplasia (AAH) is now recognized as a precursor lesion from which lung adenocarcinomas arise and thus represents an ideal target for studying the early genetic and epigenetic alterations associated with lung tumorigenesis such as alterations of the Wnt pathway.

Promoter region methylation of Wnt antagonists was common in primary lung adenocarcinoma and there was a significant increase in the frequency of methylation for Wnt antagonist genes and the number of genes methylated with each stage of tumorigenesis (test for rend P <or= 0.01).

CONCLUSION: These results show that gene silencing of Wnt antagonists by promoter hypermethylation occurs during the earliest stages of glandular neoplasia of the lung and accumulates with progression toward malignancy.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] From cystic pulmonary airway malformation, to bronchioloalveolar carcinoma and adenocarcinoma of the lung.

Bronchioloalveolar carcinoma (BAC) of the lungs is a known morphological subtype of nonsmall cell cancer.

The current study presents several carcinogenetic theories of BAC and the possible relationship with atypical adenomatous hyperplasia and congenital pulmonary airway malformation (CPAM).

The case is unique due to the combination of: early age of presentation; neoplastic transformation of a CPAM; unaltered course over 15 yrs; and its particular pattern of slow morphogenesis and degeneration into an invasive AC of the lung.

In conclusion, clinicians and pathologists need to be aware of the fact that congenital pulmonary airway malformation so far represents the only known pre-invasive lesion for mucinous bronchioloalveolar carcinoma.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Presence of local pleural adhesion in CT screening-detected small nodule in the lung periphery suggests noncancerous, inflammatory nature of the lesion.

PURPOSE: Differential diagnosis of small nodules in the lung periphery detected by low-dose chest CT screening is important before surgery.

MATERIALS AND METHODS: This study is based on 106 patients (46 men and 60 women, median age: 61.5 years) with 123 CT screening-detected and histologically confirmed nodules smaller than 30 mm in the lung periphery identified between 2002 and 2005 at Azumi General Hospital, Japan.

Lesions were classified into three groups according to histological findings: adenocarcinoma, atypical adenomatous hyperplasia (AAH) and inflammatory focal lesions.

We examined the visceral pleura during surgery at a location close to lung nodules.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Novel germline mutation: EGFR V843I in patient with multiple lung adenocarcinomas and family members with lung cancer.

A novel germline transmission of the epidermal growth factor receptor (EGFR) mutation V843I in a family with multiple members with lung cancer is reported.

These observations suggest that the germline EGFR V843I mutation might have altered EGFR signaling in the multicentric development of adenocarcinoma, bronchoalveolar carcinoma, and atypical adenomatous hyperplasia and also might have had a role in the development of lung cancer in multiple members of her family.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

BACKGROUND: We evaluated the pathologic and biological aspects of lung tumors 3.0 cm or less in diameter with the appearance of ground-glass opacity (GGO).

METHODS: Of 988 patients with non-small celllung cancer who underwent operations at our institute between January 1994 and December 2004, 87 resected lung tumor specimens that showed GGO appearance on helical computed tomography were obtained from 81 patients.

Although atypical adenomatous hyperplasia and localized bronchioloalveolar cell carcinoma of Noguchi's A and B were the predominant pathologic subtypes and nm23 negativity was rare in the pure GGO group, a high score for expression of MIB1 was often found in pure GGO tumors even though the tumors were less than 10 mm in diameter.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Localized pure or mixed ground-glass lung opacities].

Localized ground-glass opacities (GGOs) have been recently individualized and account for between 2.9% and 19% of all pulmonary nodules detected in high-risk patients included in CT screening series for lung cancer.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

OBJECTIVE: To set up animal models of the lung cancer induced by Yunnan tin mineral dusts (no radon) in F344 rats and to explore the process of carcinogenesis and pathologic alterations in various stages of malignant transformation in the animal models.

Pollak stein was used to evaluate the development of fibrosis of lung in the rats.

Along with reduction of inflammation, collagen fibrils increased at alveolar interstices.

Simple hyperplasia, papillary hyperplasia and metaplasia of the epithelial cells in alveolar and bronchi were observed, followed by atypical adenomatous hyperplasia and squamous dysplasia.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] EphA2 in the early pathogenesis and progression of non-small celllung cancer.

Overexpression of the receptor tyrosine kinase EphA2 occurs in non-small celllung cancer (NSCLC) and a number of other human cancers.

To determine if EphA2 can promote NSCLC progression, we examined the relationship of EphA2 with proliferation and migration in cell lines and with metastases in patient tumors.

Knockdown of EphA2 in NSCLC cell lines decreased proliferation (colony size) by 20% to 70% in four of five cell lines (P < 0.

04) and cell migration by 7% to 75% in five of six cell lines (P < 0. 03).

We also examined EphA2 expression in the putative premalignant lung lesion, atypical adenomatous hyperplasia, and the noninvasive bronchioloalveolar component of adenocarcinoma because K-Ras mutations occur in atypical adenomatous hyperplasia and are common in lung adenocarcinomas.

Both preinvasive lesion types expressed EphA2, showing its expression in the early pathogenesis of lung adenocarcinoma.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The serine/threonine kinase AKT and its downstream mediator mammalian target of rapamycin (mTOR) are activated in lung adenocarcinoma, and clinical trials are under way to test whether inhibition of mTOR is useful in treating lung cancer.

Here, we report that mTOR inhibition blocked malignant progression in K-ras(LA1) mice, which undergo somatic activation of the K-ras oncogene and display morphologic changes in alveolar epithelial cells that recapitulate those of precursors of human lung adenocarcinoma.

Levels of phospho-S6(Ser236/235), a downstream mediator of mTOR, increased with malignant progression (normal alveolar epithelial cells to adenocarcinoma) in K-ras(LA1) mice and in patients with lung adenocarcinoma.

Atypicalalveolarhyperplasia, an early neoplastic change, was prominently associated with macrophages and expressed high levels of phospho-S6(Ser236/235).

mTOR inhibition in K-ras(LA1) mice by treatment with the rapamycin analogue CCI-779 reduced the size and number of early epithelial neoplastic lesions (atypicalalveolarhyperplasia and adenomas) and induced apoptosis of intraepithelial macrophages.

LKR-13, a lung adenocarcinoma cell line derived from K-ras(LA1) mice, was resistant to treatment with CCI-779 in vitro.

These findings provide evidence that the expansion of lung adenocarcinoma precursors induced by oncogenic K-ras requires mTOR-dependent signaling and that host factors derived from macrophages play a critical role in adenocarcinoma progression.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Sixty-five people had a resection of their baseline screen-diagnosed lung cancers in the Early Lung Cancer Action Program.

Eighteen cases were submitted by local pathologists as Bronchioloalveolar carcinomas but were found to be invasive adenocarcinomas according to the World Health Organization classification by the Pathology Review Panel.

Eighty-three percent (76/92) of the carcinomas invaded the stroma with destruction of normal lung, and 21% (19/92) also showed either pleural or angiolymphatic invasion, even though 88% (57/65) of the carcinomas were free of lymph node metastases.

Histopathologic distinctions among atypical adenomatous hyperplasia, bronchioloalveolar carcinomas, and invasive adenocarcinoma are described in detail.

RESULTS: Strong PAR-1 staining was detected in the periphery of carcinoma nests, adenocarcinomatous emboli, foci of atypical adenomatous hyperplasia adjacent to the adenocarcinoma and atypical proliferation of duct epithelium of bronchial mucous glands.

Morphometric study demonstrated that there were significant differences of PAR-1 protein expression levels between tumors with metastatic and those without, primary and metastatic carcinomas, primary carcinomas and benign lung tissues adjacent to the carcinoma.

CONCLUSION: PAR-1 expression may play an important role in determining the malignant phenotypes of lung cancers and significantly contribute to their initiation, progression and metastasis.

Bronchioloalveolar carcinoma (BAC) appearance is a good predictor of response to this agent.

Noguchi et al. subdivided small peripheral adenocarcinoma of the lung into two groups.

One group was characterized with tumor cell growth replacing the normal alveolar cells with varying degree of fibrosis (types A-C), and the other shows non-replacing and destructive growth (types D-F).

Using probes for the 13 mutations which have been previously described, we have genotyped the EGFR gene status in surgically resected atypical adenomatous hyperplasias (AAH) and small peripheral adenocarcinomas up to 2 cm in diameter using TaqMan PCR assay.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Despite documented superiority of positron emission tomography over other investigative modalities in the preoperative staging of non-small celllung cancer, a proportion of patients will have an inaccurate staging of their mediastinal nodes.

A total of 100 consecutive patients with histologically proven non-small celllung cancer underwent staging with PET-CT prior to lung resection.

In multivariate analysis, we have identified the following as independent factors in causing inaccurate staging of mediastinal lymph nodes: rheumatoid arthritis, non-insulin dependent diabetes, history of tuberculosis, presence of atypical adenomatous hyperplasia and pneumonia (P<0.05).

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Twenty-five percent of all lung cancer cases are not attributable to smoking.

Epidermal growth factor receptor (EGFR) mutations, which are involved in approximately 50% of nonsmoker lung cancer, are positively correlated with responsiveness to gefitinib, and inversely correlated with smoking history.

Activating EGFR mutations play a critical role in the carcinogenesis of nonsmoking-related lung cancer.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Annual periodic increases in serum carcinoembryonic antigen concurrent with ground-glass opacity in the lung: report of a case.

A 63-year-old woman underwent a video-assisted thoracoscopic lobectomy for cancer of the right lung in 1999.

The following year, a lesion with ground-glass opacity was found in the left lung, and pathological examination after a partial lung resection revealed atypical adenomatous hyperplasia with expression of carcinoembryonic antigen (CEA).

Clinical evaluations, including laboratory tests, radiographic imaging, and endoscopy examinations, showed no evidence of a CEA-producing tumor, except for a new ground-glass opacity in the left lung.

To our knowledge, this is the first report of periodic increases in serum CEA levels in a patient with ground-glass opacity in the lung, not reflecting recurrence of the lung tumor.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

BACKGROUND: Low-dose spiral computed tomography (sCT) showed a four-fold increase in the detection rate in high-risk subjects and a higher percentage of stage I lung cancer in comparison with chest X-ray.

However, there is a considerable discrepancy among studies in the percentage of lung nodules, overall lung cancer and stage I detection rate.

At baseline, nodules >or=5 mm were detected in 114 (22%) undergoing sCT; the size of lung nodules ranged from 5 to 9.9 mm in 81.5% of the cases.

Five (1%) cases of lung cancer were detected.

In two additional cases a pathological diagnosis of atypical adenomatous hyperplasia was made.

Three new cases of lung cancer were detected in the second and third year of the study.

CONCLUSIONS: Despite some promising data, convincing evidence from ongoing randomized trials is needed to support the routine use of sCT as a recommended tool for screening of lung cancer.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Induction of pulmonary neoplasia in the smoke-exposed ferret by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK): a model for human lung cancer.

Research into dietary chemoprevention against lung carcinogenesis has been limited by the lack of appropriate animal models that closely mimic smoking-related human lung cancer.

Ferrets (Mustela putorius furo) have been used to study the biologic activities of carotenoids against smoke-induced lung lesions, but this model has yet to be thoroughly established and validated.

To determine the appropriateness of the ferret as a model for human lung cancer, we have performed a 6-month in vivo study in ferrets exposed to both tobacco smoke and a carcinogen (4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone, NNK) found in cigarette smoke.

Results showed that six out 12 ferrets exposed to both NNK injection and cigarette smoke developed grossly identifiable lung tumors whereas none of nine ferrets from the sham treatment group developed any lung lesions.

The histopathological types of these tumors (squamous cell carcinoma, adenosquamous carcinoma and adenocarcinoma) in ferret lungs are very similar to those in humans.

In addition, 10 out of 12 ferrets exposed to both NNK and cigarette smoke developed preneoplastic lesions (squamous metaplasia, dysplasia, and atypical adenomatous hyperplasia) with complex growth patterns whereas the sham group did not show any of these lesions.

In summary, the development of both preneoplastic lesions and gross lung tumors in ferrets provides an excellent and unique model for studying lung cancer chemoprevention with agents such as carotenoids, and for studying the molecular mechanism of carcinogenesis in the earlier stages of smoke-related lung cancer.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Epidermal growth factor receptor mutation and p53 overexpression during the multistage progression of small adenocarcinoma of the lung.

INTRODUCTION: A progression model of atypical adenomatous hyperplasia (AAH) to bronchioloalveolar carcinoma (BAC) to invasive adenocarcinoma (ADC) has been proposed.

CONCLUSIONS: High frequency and similar incidence of EGFR mutation in AAH, BAC, and ADC support that EGFR gene mutation occurs in the early stage of pulmonary ADC development and tumor initiation from the preneoplastic lung parenchyma to neoplastic conditions.

Conventional Western blotting using lysates of normal, immortalized, transformed, and tumorigenic HBEs and non-small celllung cancer cell lines confirmed some of these changes.

The expression of several of these proteins has been then analyzed by immunohistochemistry in tissue microarrays containing 323 samples, including normal bronchial epithelium, hyperplasia, squamous metaplasia, dysplasias, squamous cell carcinomas, atypical adenomatous hyperplasia, and adenocarcinomas from 144 patients.

These results indicate that the changes in proteins detected in this study may occur early in lung carcinogenesis and persist in lung cancer.

In addition, some of the proteins detected by this approach may be novel biomarkers for early detection of lung cancer and novel targets for chemoprevention or therapy.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Stepwise evolution from a focal pure pulmonary ground-glass opacity nodule into an invasive lung adenocarcinoma: an observation for more than 10 years.

The natural chronologic evolution of a lung cancer manifesting as a pure ground-glass opacity (GGO) nodule on CT scans still remains to be elucidated.

In the current case, we demonstrate serial morphologic (CT) and metabolic ((18)F-FDG PET) imaging findings in a case of adenocarcinoma, where stepwise progression from a focal pure GGO nodule (presumed atypical adenomatous hyperplasia [AAH] or bronchioloalveolar carcinoma [BAC]) eventually to an invasive adenocarcinoma was clearly depicted for more than 10-year follow-up period.

[Publication-country] Ireland

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title]Bronchioloalveolar neoplasia.

Bronchioloalveolar carcinoma (BAC) arising in the peripheral lung is the prototype of human lung adenocar-cinoma and is considered to develop, at least in part, from its precursor atypical adenomatous hyperplasia (AAH).

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] The utility of B72.3, carcinoembryonic antigen, and Leu M-1 in cell blocks: an adjunct to fine-needle aspiration diagnosis of bronchioloalveolar carcinoma of the lung.

BACKGROUND: The distinction of bronchioloalveolar carcinoma (BAC) from atypical adenomatous hyperplasia (AAH) or reactive alveolar cellhyperplasia (RAH) can be difficult on aspiration cytology, even when cell block preparations are available.

The sequential pathogenesis of lung adenocarcinomas and SCCs occurs through dissimilar phases as the former tumors typically arise in the lung periphery whereas the latter normally arise near the central airway.

METHODOLOGY/PRINCIPAL FINDINGS: We assessed the expression of SOX2, an embryonic stem cell transcriptional factor that also plays important roles in the proliferation of basal tracheal cells and whose expression is restricted to the main and central airways and bronchioles of the developing and adult mouse lung, in NSCLC by various methodologies.

Here, we found that SOX2 mRNA levels, from various published datasets, were significantly elevated in lung SCCs compared to adenocarcinomas (all p<0.001).

Moreover, a previously characterized OCT4/SOX2/NANOG signature effectively separated lung SCCs from adenocarcinomas in two independent publicly available datasets which correlated with increased SOX2 mRNA in SCCs.

Immunohistochemical analysis of various histological lung tissue specimens demonstrated marked nuclear SOX2 protein expression in all normal bronchial epithelia, alveolar bronchiolization structures and premalignant lesions in SCC development (hyperplasia, dysplasia and carcinoma in situ) and absence of expression in all normal alveoli and atypical adenomatous hyperplasias.

Furthermore, amplification of SOX2 DNA was detected in 20% of lung SCCs tested (n = 40) and in none of the adenocarcinomas (n = 17).

CONCLUSIONS/SIGNIFICANCE: Our findings highlight a cell-lineage gene expression pattern for the stem cell transcriptional factor SOX2 in the pathogenesis of lung SCCs and suggest a differential activation of stem cell-related pathways between squamous cell carcinomas and adenocarcinomas of the lung.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Using cell lines and surgical specimens of human non-small celllung cancers (NSCLCs), we here show that platelet-derived growth factor-AA (PDGF-AA) is an essential autocrine regulator for VEGF expression.

To directly assess the expression of PDGF-AA-dependent VEGF and its roles in tumorigenesis, we stably transfected established cell lines with their antisense genes.

PDGF-AA tightly regulated VEGF expression and had a greater effect on tumor size and patient prognosis than did VEGF in both cell lines and surgical sections.

PDGF-AA expression was not seen in the atypical adenomatous hyperplasia at all, whereas VEGF was occasionally seen.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

To identify the characteristics of peripheral small lung mass lesions on high-resolution computed tomography (HRCT) and discriminate between malignant and benign, 223 mass lesions 2 cm or less resected surgically were evaluated about following points.

Pure GGO lesions without scale-down between several months were all adenocarcinomas or atypical adenomatous hyperplasia (AAH).

2) Spicular or pleural indentation :75.2% (88 of 117 cases) of adenocarcinomas and all squamous cell carcinomas (18 cases) showed these findings, but 26.6% (41 of 154 cases) of positive cases were benign lesion (non-specific inflammation, mycobacterisis, and so on).

[Other-IDs] NLM/ PMC2797465

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

We have previously reported that terminal-respiratory-unit (TRU) type adenocarcinoma is a distinct subset of lung adenocarcinoma in terms of molecular pathway for carcinogenesis and phenotypic profiles.

The clinicopathologic features of gefitinib responders overlap with those of TRU-type adenocarcinoma, and the characteristics of TRU are likely to correspond to the bronchioloalveolar features reported as a predictor of gefitinib response.

In addition, EGFR mutation was detected in some cases of atypical adenomatous hyperplasia, a preinvasive lesion of TRU-type adenocarcinoma.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

All of rats in trial group (15/15) displayed atypical hyperplasia in alveolar region, showing single or multiple layers of proliferative epithelial cells along intact alveolar septa with irregular and non-discrete margins of lesion, but continuous alveolar spaces were not obliterated by proliferative epithelial cells.

Ten of 15 rats in trial group showed severe atypical hyperplasia of glandular epithelium with occasional infiltrating to muscular layer.

All of those atypical hyperplasia cells showed positive AE1/AE3 expression.

DATA SOURCES: Published literature and recent World Health Organization classification of lung tumors.

Future understanding of underlying molecular abnormalities associated with progression of these lesions into invasive lung carcinoma may result in a development of molecular assays with potential diagnostic and prognostic importance.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Bronchial and bronchioloalveolar carcinogenesis is a multicentric and multistep process, leading to a sequential accumulation of molecular and genetic abnormalities, mainly due to exposure to tobacco carcinogens.

Concomitantly, a series of morphological alterations of normal bronchial or bronchioloalveolar epithelium occur, resulting in preneoplastic and then neoplastic lesions.

Although the gradual accumulation of molecular alterations has been widely investigated in bronchial carcinogenesis, with the aim of determining new biomarkers for early lung cancer detection in high-risk patients and targeted chemoprevention, lung adenocarcinoma pathogenesis has been only recently highlighted, with the recent discovery of epidermal growth factor receptor mutation pathway in non-smokers.

This review focuses on the current status of molecular pathology in lung cancer and pulmonary preneoplastic conditions.

Chrysotile asbestos and benzo(a)pyrene (BaP) were instilled intratracheally into lung-specific dominant-negative p53 (dnp53) and control mice.

The mice were sacrificed at 12 months and their lungs examined for lung carcinomas and fibrosis.

The dnp53 mice had increased numbers of lung adenocarcinomas with BaP alone and the combination of chrysotile and BaP (the latter was additive but not significant).

Several atypical adenomatous hyperplasia lesions were found in the combined treatment group. dnp53 and FVBN control mice developed nodular buds of fibrotic lung tissue after chrysotile asbestos exposure that were localized in respiratory bronchioles; these lesions had significant increases in immunohistochemical staining for TGF-beta, MMP-7 and -9, MIG-1, and SDF-1.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Pulmonary epithelium is known to undergo a preneoplastic process prior to the development of lung carcinoma.

Squamous dysplasia and atypical adenomatous hyperplasia have been identified and classified as preinvasive lesions of squamous cell carcinoma and peripheral pulmonary adenocarcinoma, respectively.

However, these commonly recognized preinvasive lesions do not completely explain the development of all histological types of lung carcinoma.

By examining 114 resection lung specimens, we concluded that there are four histological patterns of bronchial epithelial dysplasia based on morphological features (basal cell dysplasia, columnar cell dysplasia, bronchial epithelial dysplasia with transitional differentiation, and squamous dysplasia).

Basal cell dysplasia was focally positive for cytokeratin (CK) 17 and 10/13; columnar cell dysplasia was generally positive for CK7, 8, and 18; bronchial epithelial dysplasia with transitional differentiation had a heterogeneous immunoprofile, while squamous dysplasia was positive for CK10/13 and focally positive for CK17.

By Crosstabs McNemar test, the Mann-Whitney U-test (for two independent groups), the Kruskal-Wallis one-way nonparametric ANOVA (for >2 independent groups) and Spearman correlation analysis, the degree and extent of bronchial epithelial dysplasia was shown to be positively correlated with the incidence of bronchogenic carcinoma and multifocal primary lung carcinoma (P<0.05).

(1) bronchial epithelium can develop various patterns of dysplasia with abnormal/ambiguous cell differentiation and abnormal expressions of p53 and Ki-67.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

To reveal useful prognostic factors in cases of small-sized pulmonary adenocarcinoma, we conducted a histological and karyometric analysis of 116 small-sized pulmonary adenocarcinomas measuring less than 2 cm in maximum diameter and four specimens of atypical adenomatous hyperplasia (AAH).

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Induction of lung lesions in Wistar rats by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone and its inhibition by aspirin and phenethyl isothiocyanate.

BACKGROUND: The development of effective chemopreventive agents against cigarette smoke-induced lung cancer could be greatly facilitated by suitable laboratory animal models, such as animals treated with the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK).

In the current study, we established a novel lung cancer model in Wistar rats treated with NNK.

PCNA, p63 and COX-2 expression were analyzed in the preneoplastic lung lesions.

COX-2 expression increased similarly in alveolarhyperplasia and alveolaratypical dysplasia, while PCNA expression increased more significantly in the latter than the former.

In the second study, the incidences of alveolaratypical dysplasia were reduced to 10%, 10% and 0%, respectively, in the aspirin, PEITC and aspirin and PEITC groups, compared with 62.5% in the carcinogen-treated control group.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The popularization of computed tomography (CT) in clinical practice and the introduction of mass screening for early lung cancer with the use of CT have increased the frequency of findings of subtle nodules or nodular ground-glass opacity.

Nodular ground-glass opacity may be observed in malignancies such as bronchioloalveolar carcinoma and adenocarcinoma, as well as in their putative precursors, such as atypical adenomatous hyperplasia.

The rising incidence of BAC is also reflected in recent lung cancer screening studies employing helical computed tomography (CT), where the differential diagnosis of GGOs includes not only BAC and overt adenocarcinoma, but inflammatory disease, focal fibrosis, and atypical adenomatous hyperplasia.